Drug delivery systems have evolved over the last six decades. The current drug delivery technologies have produced numerous controlled release formulations in clinical use to improve patient compliance and convenience of use with reduced side effects. While significant advances have been made in drug delivery systems, improvements are needed, particularly to increase the time period of drug delivery.
Generally, oral drug delivery systems may deliver drugs for only a day. Transdermal formulations may often deliver drugs for up to a week or so. Implantable drug delivery systems may deliver drugs for longer periods of time, ranging from weeks to months. However, because surgical implantation of long-acting drug delivery systems is not preferred, the use of microparticle formulations that may be administered using a syringe has significant benefits. For this and other reasons, injectable formulations based on microparticles, also called or microdroplets, have been developed.
Generally, a microparticle is a solid particle having a size ranging from about 1 micrometer (μm) to about 100 μm. A microdroplet generally describes an emulsion particle having a size ranging from about 1 micrometer (μm) to about 100 μm. A microdroplet and a microparticle may comprise a solvent and solid content, and the solvent may be used to dissolve the solid content within the microparticle. Additionally, the sizes of a microparticle and a microdroplet (hereinafter referred to as a “microparticle”) may be less than 1 μm or greater than 100 μm in size and may be known as a particle or a nanoparticle, respectively.
Most commercial microparticle formulations currently in clinical use have been prepared by double emulsion methods. A typical double emulsion method involves the initial dissolution of a drug in water (w) and subsequent emulsification of the drug in an organic solvent containing a biodegradable polymer. Organic solvents are referred to as oils (o). The process of emulsifying water droplets in an organic solvent is known as a water/oil (w/o) emulsion. When the stabilized w/o emulsion is placed into a larger container of water, a water/oil/water (w/o/w) double emulsion is created. The large amount of water is used to remove the organic solvent from the oil phase by extraction or by evaporation at elevated temperatures to allow the biodegradable polymer to harden. Thus, a double emulsion method is also called a double emulsion-solvent extraction or a double emulsion-solvent evaporation method.
The most commonly used biodegradable polymers for microparticle formulations are poly(lactic-co-glycolic acid) polymers, also called PLGA polymers. PLGA polymers may have different molecular weights or different Lactic:Glycolic or Lactide:Glycolide (L:G) ratios. Herein, the variety of PLGA polymers will be collectively referred to as “PLGA polymers” or simply “PLGA.”
As previously described, only about a dozen injectable long-acting microparticle formulations have been commercially developed for clinical use to date as compared to the thousands of clinically developed oral controlled release formulations. Several factors are responsible for the highly limited development of injectable microparticle formulations, particularly, the limitations and disadvantages of the double emulsion methods used to produce microparticle formulations.
Large-scale production of microparticles is very difficult to achieve via a double emulsion method. Emulsification requires high speed mixing or stirring which is challenging when the volume becomes too large. The high speed stirring, required to break up emulsion particles or droplets into smaller particles or droplets, respectively, does not allow the resulting microparticles or microdroplets to be produced at specific sizes. More typically, a broad distribution of microparticle sizes is produced from double emulsion methods from which fractions containing larger particle sizes are typically removed because they are too big to administer to a patient via a syringe needle.
In addition, the viscosity of the polymer solution in an organic solvent used in the w/o/w double emulsion method cannot be high. More specifically, the concentration of PLGA polymers dissolved in organic solvent for making w/o/w double emulsion cannot be high. The use of low PLGA concentrations results in microparticles that may not have dense matrices and may not be able to control the drug release kinetics and drug delivery to the patient.
Double emulsion methods are also often insufficient to produce microparticles containing hydrophilic drugs, particularly microparticles containing highly water-soluble drugs or large biomolecules, such as proteins and genes. Protein drugs tend to undergo denaturation at the w/o interface, leading to inactivation of the drugs. Further, most microparticle formulations prepared by double emulsion methods show an initial burst drug release that is often about two to about three orders of magnitude higher than the subsequent steady state drug release. This extremely high initial drug burst release may cause or result in serious side effects to the patient.
Limitations of the double emulsion methods described herein have been, at least in part, hampering introduction of clinically useful microparticle formulations. Accordingly, there are great demands for developing new methods for making microparticles in industrial-scale amounts. Of particular interest are methods to produce industrial or large-scale quantities of microparticles comprising desirable properties, such as high drug loading, low initial burst release, control of size, and control of release kinetics and to also avoid many of the limitations and disadvantages of double emulsion methods.
In this regard, new methods have been developed that seek to provide more control over desirable properties such as high drug loading, particle size, and control of drug release kinetics. For example, microfluidic concentric nozzle method, flow-focusing method, micro dispenser method, membrane emulsification method, and nano- or micro-fabrication methods have been developed and tested. Nano- or micro-fabrication methods include nanoimprint lithography, solvent assisted micromolding, microfluid contact printing, microcontact hot printing, step and flash imprint lithography, and particle replication in nonwetting templates. While nano- and micro-fabrication methods of microparticle production do provide some improvements over double emulsion methods such as homogeneous particle size, these methods still have limitations in drug loading capacity, initial burst release, and steady state release. An additional limitation of micro-fabrication methods of producing microparticles is the inability to control or prevent formation of a scum layer.
A scum layer is formed on a mold or surface by leakage or escape of a solution used in the micro-fabrication process of making microparticles. For example, a solvent may be leaked from a drug-polymer solution onto a membrane or mold used during microparticle formation. The leaked solvent evaporates fast resulting in a solid scum layer on the surface of the mold or membrane.
Scum layer formation on molds or membranes is a major disadvantage of micro-fabrication methods of producing microparticles. A scum layer on a mold or membrane results in unwanted loss of microparticles and drug-polymer solutions, since individual microparticles are connected to the scum layer and cannot be separated from it by agitation, sonication, or filtration. For example, formation of a scum layer during large-scale production of microparticles results in reduced microparticle yields which may be less than about 70% of the starting material.
Additionally, large-scale production of microparticles possessing such properties as controlling scum formation, drug loading capacity, initial burst release, and steady state release is still very difficult. For example, a major disadvantage of previous large-scale microparticle production processes was that the micro-cavities of the molds were manually filled with a drug-polymer mixture, which made the process rather slow and of low yields. Therefore, to manufacture industrial or large-scale quantities of drug-polymer microparticles or to scale-up the microparticle production process efficiently using polymer membrane or hydrogel mold, a swiping device and method for using the same has been developed as described herein.